An Insight on Targets and Patented Drugs for Chemotherapy of Chagas Disease

Abstract

Chagas disease or American Trypanosomiasis, a parasitic infection typically spread by triatomine bugs, affects millions of people throughout Latin America. Current chemotherapy based on the nitroaromatic compounds, benznidazole and nifurtimox provides unsatisfactory results and suffers from considerable side effects and low efficacy. Therefore, there is an urgent need for new drugs to treat this neglected disease. Over the last two decades, new advances and understanding in the biology and the biochemistry of Trypanosoma cruzi has allowed the identification of multiple targets for Chagas disease chemotherapy. This review summarizes antichagasic agents obtained based on i) target metabolic biochemical pathways or parasite specific enzymes, ii) natural products and its derivatives, iii) design and synthesis of lead compounds. Related patents filed and issued from 2000 to early 2006 are also discussed. Most of them claimed inhibitors on specific parasite targets such as cysteine proteinase, sterol biosynthesis, protein farnesyltransferase, etc. Particularly, those related to cysteine proteinase inhibitors were the most represented. Natural products also displayed many anti-T cruzi lead compounds. In addition, a few patents claiming natural or synthetic compounds with antichagasic activity, disclosed no specific target. However, only a small proportion of all these patents displayed specific data of biological trypanocidal activity.

Novel Therapeutic Strategies for Chagas` Disease

“…Recently there has been great interest in developing new cruzipain inhibitors as chemotherapeutic targets. As proof of this more than 50% of the 51 patents in the 2000-2006 period aiming at different targets for the treatment of Chagas disease, were cruzipain inhibitors (targets included: ergosterol biosynthesis inhibitors, inhibitors of polyamine and trypanothione formation) (Duschak, 2007).…”

Trypanocidal activity of flavonoids and limonoids isolated from Myrsinaceae and Meliaceae active plant extracts

“…In the past years, the study of compounds isolated from plants has received considerable attention in the search for alternative chemotherapy of parasitic diseases (Serrano et al, 2000) and many natural compounds have been identified as trypanocides (Duschak & Couto, 2007;Guimarães & Faria, 2007). Several extracts from plants of Meliaceae and Rutaceae families have been showed in vitro activity against T. cruzi (Mafezoli et al, 2000;Vieira et al, 2001;Ambrozin et al, 2004;de Mesquita et al, 2005).…”

Antichagasic Activities of Natural Products against Trypanosoma cruzi

“…Advances in our understanding of the basic biochemistry of T. cruzi have allowed the identification of new specific pathways and novel drug targets for chemotherapy, such as sterol biosynthesis, trypanothione reductase, and cystein protease. 1,[3][4][5][6] This has led to some rationally designed and synthesized candidates for the treatment of Chagas' disease. 4) On the other hand, the use of natural products for the treatment of protozoal infections is well known and long documented.…”

“…1,[3][4][5][6] This has led to some rationally designed and synthesized candidates for the treatment of Chagas' disease. 4) On the other hand, the use of natural products for the treatment of protozoal infections is well known and long documented. 4) A number of recent works reported the trypanocidal activity of a wide variety of extracts of natural medicines or its constituents.…”